Functional consequences of elimination of I-to,I-f and I-to,(s) - Early afterdepolarizations, atrioventricular block, and ventricular arrhythmias in mice lacking Kv1.4 and expressing a dominant-negative Kv4 alpha subunit

It was recently reported that the slow transient outward K+ current, I-to.s , that is evident in mouse left ventricular septal cells is eliminated in m ice with a targeted deletion of the Kv 1.4 gene (Kv1.4(-/-)). The rapidly i nactivating transient outward K+ current, I-to,I-f, in contrast, is selecti vely eliminated in ventricular myocytes isolated from transgenic mice expre ssing a dominant-negative Kv4 alpha subunit, Kv4.2W362F. Expression of Kv4. 2W362F results in marked prolongation of action potentials and QT intervals . In addition, a slow transient outward Kf current, that is similar to I-to ,I-s in wild-type mouse left ventricular septal cells, is evident in all KV 4.2W362F-expressing (left and right) ventricular cells. To test directly th e hypothesis that upregulation of Kv1.4 alpha subunit underlies the appeara nce of this slow transient outward K+ current in Kv4.2W362F-expressing vent ricular cells and to explore the functional consequences of elimination of I-to,I-f and I-to,I-s, mice expressing Kv4.2W362F in the Kv1.4(-/-) backgro und (Kv4.2W362FXKv1.4(-/-)) were generated. Histological and echocardiograp hic studies revealed no evidence of structural abnormalities or contractile dysfunction in Kv4.2W362FXKv1.4(-/-) mouse hearts. Electrophysiological re cordings from the majority ( approximate to 80%) of cells isolated from the right ventricle and left ventricular apex of Kv4.2W362FXKv1.4(-/-) animals demonstrated that both I-to,I-f and I-to,I-s are eliminated; action potent ials are prolonged significantly; and, in some cells, early afterdepolariza tions were observed. in addition, in vivo telemetric ECG recordings from Kv 4.2W362FX Ky1.4(-/-) animals revealed marked QT prolongation, atrioventricu lar block, and ventricular tachycardia. These observations demonstrate that upregulation of Kv1.4 contributes to the electrical remodeling evident in the ventricles of Kv4.2W362F-expressing mice and that elimination of both I -to,I-f and I-to,I-s has dramatic functional consequences.